Approval Sought for Ibrutinib in Waldenström's Macroglobulinemia

Peter F. Lebowitz, MD, PhD

Janssen Research & Development, LLC, has submitted a supplemental New Drug Application for ibrutinib (Imbruvica) as treatment for patients with Waldenström's macroglobulinemia (WM). If approved, it would become the 4th indication for the agent.

"We are committed to bringing our medicines to new patient populations, large and small, who may benefit from them," Peter F. Lebowitz, MD, PhD, global oncology head, Janssen, said in a statement. "By understanding the mechanism of disease and how WM was similar to other B-cell malignancies, our collaboration partner Pharmacyclics was able to pursue this submission for WM, which has the potential to make a very meaningful difference to a group of patients who do not have a sufficient number of treatment options available to them today."

Ibrutinib, which is jointly developed and commercialized by Janssen Biotech Inc. and Pharmacyclics, received a breakthrough therapy designation in February 2013 for patients with WM.

"WM is considered an orphan disease. Currently, there are no approved treatment options specifically for WM," Carl Harrington, president,,International Waldenström's Macroglobulinemia Foundation, said in a statement. "The potential approval of a WM-specific treatment will make an immense difference in our patients' lives, offering an FDA-approved option where we previously had none."

WM is a slow-growing, incurable, rare type of B-cell lymphoma for which no approved therapeutic agent exists. Approximately 1000 to 1500 patients in the US are diagnosed with WM each year and the median age at diagnosis is 60-70 years of age.

Data reported at the 2013 ASH Annual Meeting showed ibrutinib rapidly reduced serum IgM levels and improved hematocrit levels in patients with relapsed or refractory WM. However, patients who harbored a WHIM-like mutation of CXCR4, present in about 30% of patients with WM, were less like to respond to the agent.

As part of the study, 63 patients with relapsed/refractory WM received 420 mg/day oral ibrutinib for up to 2 years until disease progression or unacceptable toxicity. At baseline, patients’ mean hemoglobin level was 10.5 mg/dL and mean serum IgM level was 3610. Anemia was the most common reason for treatment initiation (87.3% of patients).

With a median follow-up of 9 cycles, the best overall response rate (minor response or better using consensus criteria adapted from the 3rd International Workshop on WM) was 83%, with a major response rate (partial response or better) of 64.0%.

The agent was also well tolerated in this population. The most common grade ≥2 treatment-related toxicities were thrombocytopenia (n = 10) and neutropenia (n = 12), which occurred most commonly in heavily pretreated patients. Most bleeding events occurred in patients taking concomitant fish oil supplements.

Ibrutinib is currently approved for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy and for the treatment of CLL patients with del 17p. The agent is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy.